2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses

ABSTRACT

The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives. Particularly the invention concerns novel intermediates and their use in methods for the preparation of S-α-ethyl-2-oxo-1-pyrrolidine acetamide.

[0001] The invention concerns 2-oxo-1-pyrrolidine derivatives and aprocess for preparing them and their uses. The invention also concerns aprocess for preparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivativesfrom unsaturated 2-oxo-1-pyrrolidine derivatives.

[0002] Particularly the invention concerns novel intermediates and theiruse in methods for the preparation of(S)-(−)-α-ethyl-2-oxo-1-pyrrolidine acetamide, which is referred underthe International Nonproprietary Name of Levetiracetam, itsdextrorotatory enantiomer and related compounds. Levetiracetam is shownas having the following structure:

[0003] Levetiracetam, a laevorotary compound is disclosed as aprotective agent for the treatment and the prevention of hypoxic andischemic type aggressions of the central nervous system in the Europeanpatent No. 162036. This compound is also effective in the treatment ofepilepsy, a therapeutic indication for which it has been demonstratedthat its dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidineacetamide completely lacks activity (A. J. GOWER et al., Eur. J.Pharmacol., 222, (1992), 193-203). Finally, in the European patentapplication No. 0 645 139 this compound has been disclosed for itsanxiolytic activity.

[0004] The asymmetric carbon atom carries a hydrogen atom (not shown)positioned above the plane of the paper. The preparation ofLevetiracetam has been described in the European patent No. 0162 036 andin the British patent No. 2 225 322, both of which are assigned to theassignee of the present invention. The preparation of the dextrorotatoryenantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamide has beendescribed in the European patent No. 0165 919. Nevertheless, theseapproaches do not fully satisfy the requirements for an industrialprocess. Therefore, a new approach has been developed via the asymmetrichydrogenation of new precursors.

[0005] In one aspect, the invention provides a compound having thegeneral formula (A) and pharmaceutically acceptable salts thereof,

[0006] wherein X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN;

[0007] R¹ is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl,halogen, hydroxy, amino, nitro, cyano;

[0008] R², R³, R⁴, are the same or different and each is independentlyhydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy,sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonicacid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylsulfinyl, arylsulfinyl, alklylthio, arylthio, alkyl, alkoxy,oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, vinyl;

[0009] R⁵, R⁶, R⁷ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy,aryloxy; and

[0010] R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl,heterocycloalkyl, heteroaryl, alkylthio, arylthio.

[0011] The term alkyl as used herein, includes saturated monovalenthydrocarbon radicals having straight, branched or cyclic moieties orcombinations thereof and contains 1-20 carbon atoms, preferably 1-5carbon atoms. The alkyl group may optionally be substituted by 1 to 5substituents independently selected from the group consisting halogen,hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl,alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide,alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl,arylsulfinyl, alkylthio, arylthio, oxyester, oxyamido, heterocycloalkyl,heteroaryl, vinyl, (C1-C5)alkoxy, (C6-C10)aryloxy, (C6-C10)aryl.Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least agroup selected from halogen, hydroxy, thiol, amino, nitro, cyano, suchas trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

[0012] The term “heterocycloalkyl”, as used herein, represents an“(C1-C6)cycloalkyl” as defined above, having at least one O, S and/or Natom interrupting the carbocyclic ring structure such astetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl,morpholino and pyrrolidinyl groups or the same substituted by at least agroup selected from halogen, hydroxy, thiol, amino, nitro, cyano.

[0013] The term “alkoxy”, as used herein includes —O-alkyl groupswherein “alkyl” is defined above. Preferred alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least a halo group such astrifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

[0014] The term “alkylthio” as used herein, includes —S-alkyl groupswherein “alkyl” is defined above. Preferred alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least a halo group, such astrifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

[0015] The term “alkylamino” as used herein, includes —NHalkyl or—N(alkyl)₂ groups wherein “alkyl” is defined above. Preferred alkylgroups are methyl, ethyl, n-propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.

[0016] The term “aryl” as used herein, includes an organic radicalderived from an aromatic hydrocarbon by removal of one hydrogen, such asphenyl, phenoxy, naphthyl, arylalky, benzyl, optionally substituted by 1to 5 substituents independently selected from the group halogen,hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl,alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide,alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester,oxyamido, aryl, (C1-C6)alkoxy, (C6-C10)aryloxy and (C1-C6)alkyl. Thearyl radical consists of 1-3 rings preferably one ring and contains 2-30carbon atoms preferably 6-10 carbon atoms. Preferred aryl groups are,phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl,benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl,2-phenylethyl.

[0017] The term “arylamino” as used herein, includes —NHaryl or—N(aryl)₂ groups wherein “aryl” is defined above. Preferred aryl groupsare, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl,benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl,2-phenylethyl.

[0018] The term “aryloxy”, as used herein, includes —O-aryl groupswherein “aryl” is defined as above. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0019] The term “arylthio”, as used herein, includes —S-aryl groupswherein “aryl” is defined as above. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0020] The term “halogen”, as used herein, includes an atom of Cl, Br,F, I.

[0021] The term “hydroxy”, as used herein, represents a group of theformula —OH.

[0022] The term “thiol”, as used herein, represents a group of theformula —SH.

[0023] The term “cyano”, as used herein, represents a group of theformula —CN.

[0024] The term “nitro”, as used herein, represents a group of theformula —NO₂.

[0025] The term “amino”, as used herein, represents a group of theformula —NH₂.

[0026] The term “carboxy”, as used herein, represents a group of theformula —COOH.

[0027] The term “sulfonic acid”, as used herein, represents a group ofthe formula —SO₃H.

[0028] The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

[0029] The term “heteroaryl”, as used herein, unless otherwiseindicated, represents an “aryl” as defined above, having at least one O,S and/or N interrupting the carbocyclic ring structure, such as pyridyl,furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isobenzofuryl,benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, or benzoxazolyl,optionally substituted by 1 to 5 substituents independently selectedfrom the group consisting hydroxy, halogen, thiol, amino, nitro, cyano,acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether,amido, sulfonic acid, sulfonamide, alkylsulfonyl, alkoxycarbonyl,oxyester, oxyamido, alkoxycarbonyl, (C1-C5)alkoxy, and (C1-C5)alkyl.

[0030] The term “arylalkyl” as used herein represents a group of theformula aryl-(C1-C4 alkyl)-. Preferred arylalkyl groups are, benzyl,halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl,diphenylmethyl, (4-methoxyphenyl)diphenylmethyl.

[0031] The term “acyl” as used herein, represents a radical ofcarboxylic acid and thus includes groups of the formula alky-CO—,aryl-CO—, heteroaryl-CO—, arylalkyl-CO—, wherein the various hydrocarbonradicals are as defined in this section. Preferred alkyl groups aremethyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

[0032] The term “oxyacyl” as used herein, represents a radical ofcarboxylic acid and thus includes groups of the formula alky-CO—O—,aryl-CO—O—, heteroaryl-CO—O—, arylalkyl-CO—O—, wherein the varioushydrocarbon radicals are as defined in this section. Preferred alky andaryl groups are the same as those defined for the acyl group.

[0033] The term “sulfonyl” represents a group of the formula —SO₂-alkylor —SO₂-aryl wherein “alkyl” and “aryl” are defined above. Preferredalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl,nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl,methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0034] The term “sulfinyl” represents a group of the formula —SO-alkylor —SO-aryl wherein “alkyl” and “aryl” are defined above. Preferredalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl,nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl,methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0035] The term “ester” means a group of formula —COO-alkyl, or—COO-aryl wherein “alkyl” and “aryl” are defined above. Preferred alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo group.Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl,methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl,nitrobenzyl, 2-phenylethyl.

[0036] The term “oxyester” means a group of formula —O—COO-alkyl, or—O—COO-aryl wherein “alkyl” and “aryl” are defined above. Preferredallyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl,nitrophenyl, methoxyphenyl benzyl, halobenzyl, cyanobenzyl,methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0037] The term “ether” means a group of formula alkyl-O-alkyl oralkyl-O-aryl or aryl-O-aryl wherein “alkyl” and “aryl” are definedabove. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted byat least a halo group. Preferred aryl groups are, phenyl, halophenyl,cyanophenyl, nitrophenyl, methoxyphenyl benzyl, halobenzyl, cyanobenzyl,methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0038] The term “amido” means a group of formula —CONH₂ or —CONHalkyl or—CON(alkyl)₂ or —CONHaryl or —CON(aryl)₂ wherein “aryl” and “aryl” aredefined above. Preferably alkyl has 1-4 carbon atoms and aryl has 6-10carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the samesubstituted by at least a halo group. Preferred aryl groups are, phenyl,halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl,cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.

[0039] The term “oxyamido” “means a group of formula —O—CONH2 or—O—CONHalkyl or —O—CON(alkyl)2 or —O—CONHaryl or —O—CON(aryl)2 wherein“alkyl” and “aryl” are defined above. Preferably alkyl has 1-5 carbonatoms and aryl has 6-8 carbon atoms. Preferred alkyl groups are methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least a halo group. Preferred aryl groupsare, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl,benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl,2-phenylethyl.

[0040] Preferably R¹ is methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least ahalogen group such as trifluoromethyl trichloromethyl,2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

[0041] Preferably R², R³ and R⁴ are independently hydrogen or halogen ormethyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least a halo groupsuch as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

[0042] Preferably R⁵ and R⁶ are independently hydrogen, methyl, ethyl,propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl.

[0043] Preferably R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl,butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl,benzyl or the same substituted by at least a halo group such astrifluoromethyl, chlorophenyl.

[0044] Preferably R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl,butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or thesame substituted by at least a halo group such as trifluoromethyl,chlorobenzyl or where X is —CN.

[0045] Unless otherwise stated, references herein to the compounds ofgeneral formula (A) either individually or collectively are intended toinclude geometrical isomers i.e. both Z (Zusammen) and E (Entgegen)isomers and mixtures thereof (racemates).

[0046] With respect to the asymmetric hydrogenation process describedbelow, the best results have been obtained for the Z (Zusammen) and E(Entgegen) isomers of the compounds of formula (A) where R¹ is methyl,R²and R⁴ are H and X is —CONH₂ or —COOMe or —COOEt or —COOH. Within thisgroup, compounds wherein R³ is hydrogen, alkyl (especially propyl) orhaloalkenyl (especially difluorovinyl) are particularly well suited.

[0047] An aspect of the invention concerns a process for preparing thecompound having a general formula (A). This process includes thefollowing reactions:

[0048] Compounds having a general formula (A), where X is —CONR⁵R⁶ or—COOR⁷ or —CO—R⁸ or CN, may conveniently be made by reaction of anα-ketocarboxylic acid derivative of general formula (C) where R¹ and Xare described above, with a pyrrolidinone of general formula (D) whereR², R³, R⁴ are described above, according to the following scheme (1).

[0049] Compounds having a general formula (A) where X is —COOR⁷ mayconveniently be made by reaction of an α-ketocarboxylic acid derivativeof general formula (C′) where X is —COOR⁷ with a pyrrolidinone ofgeneral formula (D) according to the following scheme (2).

[0050] Suitable reaction conditions involve use of toluene under reflux.In the resulting compound (A), R⁷ may readily be converted from H toalkyl or from alkyl to H.

[0051] Derivatives of general formula (C) or (C′) and pyrrolidones ofgeneral formula (D) are well known by the man of the art and can beprepared according to syntheses referred to in the literature, such asin “Handbook of Heterocyclic Chemistry” by A. Katrisky, Pergamon, 1985(Chapter 4.) and in “Comprehensive Heterocyclic Chemistry” by A.Katrisky & C. W. Rees, Pergamon. 1984 (Volume 4, Chapters 3.03 & 3.06).

[0052] Compounds of general formula (A) where X is —CONH₂ or —CONR⁵R⁶may conveniently be prepared by conversion of the corresponding acid(compound of formula (A) where X is CO₂H) to the acid chloride withsubsequent ammonolysis or reaction with a primary or secondary amine ofthe general formula HNR⁵R⁶. The following two schemes (3 and 4) describesuch a process.

[0053] These reactions are preferably performed using PCl₅ to give anacid chloride followed by anhydrous ammonia or primary or secondaryamine of the formula HNR⁵R⁶ to give the desired enamide amide.

[0054] Compounds of general formula (A) where X is —COOR⁷ mayconveniently be made by conversion of the corresponding acid (compound(A) where X is COOH) obtained by Scheme (2) to the acid chloride withsubsequent alcoholysis with the compound of formula R⁷—OH (alcohol)where R⁷ is defined above. (see Scheme 5)

[0055] These reactions are preferably performed using PCl₅ to give anacid chloride followed by alcoholysis with R⁷—OH to give the desiredester.

[0056] The conditions of the above reactions are well known by the manskilled in the art.

[0057] In another aspect the invention concerns the use of compounds offormula (A) as synthesis intermediates.

[0058] The compound of formula (A) where X is —CONH₂ is of particularinterest, as catalytic hydrogenation of this compound leads directly toLevetiracetam. Both the Z (Zusammen) and E (Entgegen) isomers of thesecompounds have been shown to undergo rapid and selective asymmetrichydrogenation to either enantiomer of the desired product. Therepresentation of the bond joining the group R¹ to the molecule denoteseither a Z isomer or an E isomer

[0059] As a particular example, the use of compounds (A) for thesynthesis of compounds (B) may be illustrated according to the followingscheme (6).

[0060] wherein R¹, R², R³, R⁴ and X are as noted above.

[0061] Preferably, R¹ is methyl, ethyl, propyl, isopropyl, butyl, orisobutyl; most preferably methyl, ethyl or n-propyl.

[0062] Preferably, R² and R⁴ are independently hydrogen or halogen ormethyl, ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably,are each hydrogen.

[0063] Preferably, R³ is C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl,cyclopropyl, azido, each optionally substituded by one or more halogen,cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl;phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienylfurryl, pyrrole, pyridine, whereby any phenyl moiety may be substitutedby one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/orphenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, orisobutyl.

[0064] Preferably, X is —COOH or —COOMe or —COOEt or —CONH₂; mostpreferably —CONH₂.

[0065] The compounds of formula (B) may be isolated in free form orconverted into their pharmaceutically acceptable salts, or vice versa,in conventional manner.

[0066] Preferred individual compounds among the compounds having thegeneral formula (B) have the formulas (B′),(B″) and (B′″).

[0067] The compounds of formula (B) are suitable for use in thetreatment of epilepsy and related ailments. According to anotherembodiment, the invention therefore concerns a process for preparing acompound having a formula (B)

[0068] wherein R¹, R², R³, R⁴ and X are as noted above, via catalyticassymetric hydrogenation of the corresponding compound having theformula (A) as illustrated and defined above. Catalytic hydrogenation isdescribed in many publications or books such as “Synthese et catalyseasymetriques—auxiliaires et ligands chiraux” Jacqueline Seyden-Penne(1994)—Savoirs actuel, interEdition/CNRS Edition—CH 7.1 “hydrogenationcatalytique” page 287-300.

[0069] Unless otherwise stated, references herein to the compounds ofgeneral formula (B) either individually or collectively are intended toinclude geometrical isomers i.e. both Z (Zusammen) and E (Entgegen)isomers as well as enantiomers, diastereoisomers and mixtures of each ofthese (racemates).

[0070] Preferably, the process of the invention concerns the preparationof compounds of formula (B) in which R²and R⁴ are hydrogen and X is—COOH or —COOMe or —COOEt or —CONH₂and R¹ is methyl particularly thosewherein R³ is hydrogen, alkyl (especially propyl) or haloalkenyl(especially difluorovinyl). Best results have been obtained with theprocess for preparing levetiracetam, compoung of formula (B) in which R¹is methyl, R²and R⁴ are hydrogen, R³ hydrogen, propyl or difluorovinyland X is —CONH₂.

[0071] Generally, this process comprises subjecting to catalytichydrogenation a compound of formula (A) as described above. Preferablythe compound of formula (A) is subjected to asymmetric hydrogenationusing a chiral catalyst based on a rhodium (Rh) or ruthenium (Ru)chelate. Asymmetric hydrogenation methods are described in manypublications or books such as “Asymmetric Synthesis” R. A Aitken and S.N. Kilenyi (1992)—Blackie Academic & Professional or “Synthesis ofOptically active—Amino Acids” Robert M. Willimas (1989)—Pergamon Press.

[0072] Rh(I)-, and Ru(II)-, complexes of chiral chelating ligands,generally diphosphines, have great success in the asymmetrichydrogenation of olefins. Many chiral bidentate ligands, such asdiphosphinites, bis(aminophosphine) and aminophosphine phosphinites, orchiral catalyst complexes, are described in the literature or arecommercially available. The chiral catalyst may also be associated to acounterion and/or an olefin.

[0073] Although much information on the catalytic activity andstereoselectivity of the chiral catalysts has been accumulated, thechoice of the ligands, the chiral catalysts and reaction conditionsstill has to be made empirically for each individual substrate.Generally the Rh(I) based systems are mostly used for the preparation ofamino acid derivatives, while the Ru(II) catalysts give good toexcellent results with a much broader group of olefinic substrates.Chiral catalyst chelators which may be used in the present invention,are DUPHOS, BPPM, BICP, BINAP, DIPAMP, SKEWPHOS, BPPFA, DIOP, NORPHOS,PROPHOS, PENNPHOS, QUPHOS, BPPMC, BPPFA. In addition to this, supportedor otherwise immobilised catalysts prepared from the above chelators mayalso be used in the present invention in order to give either improvedconversion or selectivity, in addition to improved catalyst recovery andrecycling. Preferred chiral catalyst chelators for use in the method ofthis invention are selected from DUPHOS or Methyl, Diethyl,Diisopropyl-DUPHOS (1,2-bis-(2,5-dimethylphospholano)benzene—U.S. Pat.No. 5,171,892), DIPAMP (Phosphine, 1,2-ethanediylbis((2-methoxyphenyl)phenyl—U.S. Pat. No. 4,008,281 and No. 4,142,992),BPPM (1-Pyrrolidinecarboxylic acid,4-(diphenylphosphino)-2-((diphenylphosphino)methyl)-, 1,1-dimethylethylester—Japanese patent N^(o) 87045238) and BINAP (Phosphine,(1,1′-binaphthalene)-2,2′-diylbis(diphenyl—European patent No. 0 366390).

[0074] The structures of these chelators are shown below.

[0075] Preferred solvents for use in the method of this invention areselected from, tetrahydrofuran (THF), dimethylformamide (DMF), ethanol,methanol, dichloromethane (DCM), isopropanol (IPA), toluene, ethylacetate (AcOEt).

[0076] The counterion is selected from halide (halogen(−)), BPh₄(−)ClO₄(−), BF₄(−), PF₆(−), PCl₆(−), OAc(−), triflate (OTf(−)), mesylate ortosylate. Preferred counterions for use with these chiral catalysts areselected from OTf(−), BF4(−) or OAc(−).

[0077] The olefin is selected from ethylene, 1,3-butadiene, benzene,cyclohexadiene, norbornadiene or cycloocta-1,5-diene (COD).

[0078] Using these chiral catalysts, in combination with a range ofcounter-ions and at catalyst-substrate ratios ranging from 1:20 to1:20,000 in a range of commercially available solvents it is possible toconvert compounds of formula (A) into laevorotary or dextrorotaryenantiomers of compounds of formula (B) having high % of enantiomericexcess (e.e.) and in excellent yield, and high purity. Moreover, thisapproach will use standard industrial plant and equipment and have costadvantages.

[0079] This asymmetric synthesis process will also be lower cost due tothe avoidance of recycling or discarding the unwanted enantiomerobtained by a conventional synthesis process.

[0080] Best results have been obtained with the process for preparing(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide or(R)-α-ethyl-2-oxo-1-pyrrolidineacetamide, wherein it comprisessubjecting a compound of formula A′ in the form of a Z isomer or an Eisomer to asymmetric hydrogenation using a chiral catalyst according tothe following scheme.

[0081] In what follows, reference is made particularly to four compoundsof formula (A) in which R¹ is methyl, R², R³ and R⁴ are hydrogen and,

[0082] for the compound hereinafter identified as precursor A1, X is—COOH;

[0083] for the compound hereinafter identified as precursor A2, X is—COOMe;

[0084] for the compound hereinafter identified as precursor A2′, X is—COOEt; and

[0085] for the compound hereinafter identified as precursor A3, X is—CONH₂.

[0086] As will be appreciated by the skilled person, depending on thesubstitution pattern, not all compounds of general formula (A) and (B)will be capable of forming salts so that reference to “pharmaceuticallyacceptable salts” applies only to such compounds of general formulae (A)or (B) having this capability.

[0087] The following examples are provided for illustrative purposesonly and are not intended, nor should they be construed, as limiting theinvention in any manner. Those skilled in the art will appreciate thatroutine variations and modifications of the following examples can bemade without exceeding the spirit or scope of the invention.

EXAMPLE 1

[0088] The preparation of precursor A1 was carried out in 70% crudeyield by reacting α-ketobutyric acid and pyrrolidinone in refluxingtoluene, see Scheme 7. By Z:E, we mean the ratio of Z isomer amount on Eisomer amount.

[0089] The crude product was recrystallised from acetone in 70% yield.The geometry of the double bond was assigned to be Z on the basis ofcorrelation with the ¹H-NMR (Nuclear Magnetic Resonance) spectral datafor known compounds with similar structure.

EXAMPLE 2

[0090] Precursor A2 was prepared from A1 with diazomethane in THF. Itwas observed that the Z-E ratio changes from 80:1 to 29:1 duringdistillation (see Scheme 8).

[0091] The E-isomer of precursor A₂′ has been obtained as shown inScheme 9 from Z-isomer of precursor A₁ with ethanol,dicyclohexylcarbodiimide (DCC) and dimethylaminopyrydine (DMAP).

[0092] Esterification of precursor A₁ was also carried out on a smallscale with PCl₅ in THF then MeOH and gave exclusively the desired methylesters (E:Z=5:1), see Scheme 10.

EXAMPLE 3

[0093] Precursor A2 was also prepared by reacting ketobutyric acidmethyl ester and pyrrolidinone in refluxing toluene in the presence of acatalytic amount of POCl₃, see Scheme 11.

[0094] The esterification of the ketobutyric acid was carried out eitherwith methanol following a literature method, or with diazomethane. Thesubsequent condensation reaction gave precursor A2 in 60% yield. Thismethod leads to a higher content of E-isomer in comparison to the routevia precursor A1 (Scheme 8). Both routes allow for the preparation ofother ester derivatives of precursor A2.

EXAMPLE 4

[0095] Synthesis of the precursor A3 has been effected by reacting theenamide acid with PCl₅ to give the acid chloride and then with gaseousammonia to obtain the desired enamide amide A3. The product has beenconfirmed as the Z-isomer.

[0096] The crude enamide amide A3 was isolated from the reaction mixtureby dissolving it in THF-MeOH and filtering to remove inorganic residues.After evaporation of the solvent a yellow solid was obtained. The crudematerial was purified by dry flash chromatography followed byrecrystallisation from i-PrOH to afford pure material. This procedurehas been successfully applied to produce a single batch of A3 (118 g,54%, >99% by peak area) and is outlined in Scheme 12.

[0097] In most cases of the asymmetric hydrogenation of precursors, thecatalyst has been prepared in situ by reacting [Rh(COD)₂]⁺OTf⁻ and therespective chiral ligand in the solvent of choice followed by additionof substrate. Some catalysts are commercially available and these havebeen used without further purification.

EXAMPLE 5

[0098] Results from the asymmetric hydrogenation of precursors A1 and A2using a number of rhodium based catalyst systems are summarised in thefollowing Table 1. These reactions have been performed with between0.005 mol % and 5 mol % of catalyst and 100 mg or 200 mg of substrate atambient temperature (room temperature: rt) for 24 hours. Reactionconditions such as the H₂ pressure, the kind of solvents, the amount ofprecursor have been modified in order to obtain the optimal conditions.All products have been isolated by evaporation of the solvent from thereaction mixture and analysed without further purification by ¹H-NMRspectroscopy.

[0099] The HPLC (High Performance Liquid Chromatography) method for %e.e. determination of the hydrogenation product of precursor A1 proveddifficult to develop. Therefore, we converted the crude products intotheir methyl esters using diazomethane in THF solution. The esterderivatives were then analysed using a chiral HPLC method for monitoringthe hydrogenation of enamide ester A2. For the HPLC method, we used aChiracel OD 4.6×250 mm column and IPA/n-hexane (95:05) as eluant.

[0100] For the hydrogenated product of precursor A2, the e.e. resultshave been obtained by the following chiral HPLC method: Chiralcel OD4.6×250 mm, IPA-Hexane (5:95 v/v), 205 nm, 1 ml/min at ambienttemperature (rt). sample 1 mg/ml, 13 min (S-enantiomer), 16 min(R-enantiomer). Initially, the screening was carried out on 100 mg scalewith 5 mol % of catalyst.

[0101] The results in % of enantiomeric excess (e.e.) are positive toexpress the percentage of laevorotatory S-enantiomer and negative toexpress the percentage of dextrorotatory R-enantiomer. TABLE 1 St. Am.H2 Ma. Mg Catalyst Cou. Loa. Solv. Pres. C.V. % e.e. % A1 100(S,S)-Et-DUPHOS OTf(−) 5.0 EtOH 4 100 95 A1 100 (S,S)-BPPM OTf(−) 5.0EtOH 1 68 −64 A1 100 (R,R)-DIPAMP BF4(−) 5.0 DCM 4 100 92 A2 (Z) 200(S,S)-Et-DUPHOS OTf(−) 2.0 EtOH 4 100 98.8 A2 (Z) 200 (S,S)-Et-DUPHOSOTf(−) 0.5 EtOH 4 100 99.1 A2 (Z) 200 (S,S)-Me-DUPHOS OTf(−) 1.0 EtOH 5100 98.9 A2 (Z) 300 (S,S)-Me-DUPHOS OTf(−) 2.0 IPA 5 100 97.9 A2′ (E)200 (S,S)-Me-DUPHOS OTf(−) 0.5 EtOH 5 100 99.4 A2′ (E) 300(S,S)-Me-DUPHOS OTf(−) 0.5 IPA 5 100 94.0 A2 (E) 4000 (S,S)-Me-DUPHOSBF4(−) 0.025 MeOH 5 100 97.4 A2 (Z) 4000 (S,S)-Me-DUPHOS BF4(−) 0.01MeOH 5 99 99 A2 (Z) 4000 (S,S)-Me-DUPHOS BF4(−) 0.005 MeOH 5 25 97 A2′(E) 300 (S,S)-BPPM OTf(−) 0.5 MeOH 1 100 −99.3 A2′ (E) 300 (S,S)-BPPMOTf(−) 0.5 EtOAc 1 100 −95.2 A2 (E) 300 (S,S)-BPPM OTf(−) 0.5 Toluene 1100 −96.2 A2 (Z) 200 (R,R)-DIPAMP BF4(−) 2.0 EtOAc 5 100 94.5 A2′ (E)200 (R,R)-DIPAMP BF4(−) 0.5 EtOAc 5 92 96.5

EXAMPLE 6 Asymmetric Hydrogenation of Precursor A3

[0102] Using the same approach as in example 5; a number of rhodium andruthenium catalysts have been screened, see Scheme 13 and Table 2 forrepresentative results. TABLE 2 Amount Loa. H₂ Reaction A3 mol Pres.time Reaction e.e. mg Catalyst metal Cou. % solvent volume atm hourstemp. Conversion % % 100 (R)-BINAP Ru OAc(−) 2.5 EtOH 25 4.5 16 rt 100−82.7 500 (R)-BINAP Ru OAc(−) 1.0 EtOH/H₂O 20 4 16 rt 100 −85 5:1 500(R,R)-DIPAMP Rh BF4(−) 0.5 DCM 20 4 18 rt 80-90 90 500 (R,R)-DIPAMP RhBF4(−) 1.0 DCM 20 4 18 rt 100 93 500 (R,R)-DIPAMP Rh BF4(−) 2.5 DCM 20 470 rt 100 94.4 500 (R,R)-DIPAMP Rh BF4(−) 2.5 EtOH 20 4 70 rt 100 93.8500 (R,R)-DIPAMP Rh BF4(−) 1.0 EtOH 20 4 16 rt 100 85 2000 (S,S)-BPPM RhOTf(−) 0.5 EtOH 10 1 40 65-70° C. 100 −7 500 (S,S)-Et-DUPHOS Rh OTf(−)0.5 DCM 40 4 16 rt 100 97 500 (S,S)-Et-DUPHOS Rh OTf(−) 2.5 DCM 40 4 17rt 100 97

[0103] As above, the rhodium catalysts have been prepared in situ orpurchased and used without further purification. The ruthenium catalystswere prepared according to known literature procedures. Most experimentshave been conducted on a 100 mg to 15 g scale with between 0.001 mol %and 5 mol % of catalyst. The crude products have been analysed by ¹H,¹³C NMR spectroscopy and by chiral HPLC analysis.

EXAMPLE 7 Asymmetric Hydrogenation of Precursor A3 withRh-(Et,Et)-DUPHOS

[0104] The results of the hydrogenation of A3 with Rh-DUPHOS catalystare shown in Table 3. These reactions have been performed in the sameway as in example 5 and 6, with a hydrogen pressure of 4 atmospheres.

[0105] Usually, enantioselectivities in the Rh-DUPHOS catalysedhydrogenations of α-acylaminoacrylic acid derivatives show very littlesolvent effect. However, it remains impossible to predict a priori whatthe effect of the solvent would be on the enantioselectivity and therate of the reaction for a given substrate. It has been observed thatthe hydrogenation of A3 is highly solvent dependant. Thenon-coordinating, aprotic solvent DCM was found superior. Hydrogenationsin protic alcoholic solvents resulted in slower reactions and reducedselectivity. Similarly, reduced conversions were observed in polaraprotic solvents such as EtOAc and THF, both of which may be expected tocoordinate to the metal and inhibit catalysis. The inhibition bycoordinating solvents probably suggests that A3 is a poorly coordinatingsubstrate, especially in comparison to other α-acylaminoacrylic acidderivatives.

[0106] Nevertheless, excellent results have been obtained in DCM. As canbe seen, enantioselectivities of 97 to 98% e.e. were consistentlyachieved on 0.5 to 15 g scale in this solvent. Other promising resultswere obtained in EtOAc-DCM solvent mixture and in toluene. TABLE 3Hydrogenation of A3 with [Rh-COD-(S,S)-Et DUPHOS]OTf Amount Reaction A3Catalyst solvent time mg mol % solvent volume (hours) C.V. % e.e. % 5001.0 AcOEt/DCM 30 17 95 96 5:1 500 1.0 DCM 20 17 100 97 500 0.5 DCM 30 1699 98 500 0.5 DCM 40 16 100 97 500 2.5 DCM 40 17 100 97 10000 1.0Toluene 30 65 93 92 500 1.0 Toluene 30 16 95 95

A. Preparation of Precursor A1:(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoic acid (Precursor A1)

[0107] A 1 l flask fitted with a magnetic stirring bar and a Dean-Starktrap was charged with 2-oxobutanoic acid (25 g, 245 mmol), toluene (500ml, 20 vol) and 2-pyrrolidinone (37.2 ml, 490 mmol, 2 equiv). Thereaction mixture was stirred under reflux with azeotropic removal ofwater via the Dean-Stark trap for 5.5 hours. The solution was thenconcentrated to ca. 90 ml (3.6 vol) and allowed to cool slowly toambient temperature. Off-white solid started to come out of solution ataround 55° C. The solid was filtered, the cake was washed with toluene(2×1 vol) followed by dichloromethane (3×1 vol) and dried on the filterunder vacuum for 5 min to afford crude material (28 g. 70% yield). Thecrude product was dissolved in acetone (450 ml. 16 vol) at reflux,cooled slowly to ambient temperature and allowed to crystallise over 12hrs at −15 to −20° C. Pure product was obtained as a white crystallinesolid (21 g, 51% overall yield).

[0108] Melting point (m.p.). 165.5-166° C.

[0109]¹H NMR (CDCl₃): δ (chemical shift) 2.13 (5H, doublet (d) andmultiplet), 2.51(2H, triplet (t)), 3.61(2H, t). 6.27(1H, quadruplet(q)), 8 to 10(1H, broad); signals for E-isomer, δ 1.85(3H, t), 7.18(1H,q).

[0110]¹³C NMR(MeOH-d4): δ 14.7, 19.6, 32.1, 51.4, 130.8, 137.7, 166.6,177.9.

[0111] Z:E ratio 149:1, by ¹H NMR.

[0112] Thin Layer Chromatography (TLC): SiO₂, Toluene/AcOH/MeOH(4:1:0.5), UV and anisaldehyde stain.

B. Preparation of Precursor A2: Methyl(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

[0113] Precursor A1 (12 g, 71 mmol) was dissolved in THF (240 ml, 20vol) at 0-5° C. A solution of diazomethane in ether (200 ml, ˜78 mmol,1.1 equiv) was added portionwise to the reaction mixture, keeping thetemperature below 5° C. The reaction mixture turned yellow colour withthe last portion of the reagent. This was stirred for additional 30 minat low temperature and then allowed to warm up. The remaining traces ofdiazomethane were destroyed by dropwise addition of very dilute aceticacid in THF until the yellow solution became colourless. The reactionmixture was concentrated in vacuo and the crude material was distilled(93-94° C., 0.01 mm Hg) to afford pure product (9.44 g, 73%) as acolourless oil, which solidifies on cooling below 10° C.

[0114]¹H NMR (CDCl₃): δ 2.0(3H, d), 2.1(2H, m), 2.43(2H, t), 3.54(2H,t), 3.76(3H, s), 5.96(1H, q); signals for E-isomer, δ 1.75(3H, d) and7.05(1H, q).

[0115]¹³C NMR(MeOH-d4): δ 14.4, 19.7, 32, 51, 52.6, 130.1, 134.4, 165.6,177.4. Z:E ratio 29:1 by ¹H NMR.

C. Preparation of methyl 2-oxobutanoate

[0116] 2-Oxobutanoic acid (15 g) was distilled under reduced pressureusing a Kugelruhr apparatus (84° C., 20 mm Hg) to yield 14 g of purifiedmaterial. Distilled 2-oxobutanoic acid (14 g) was dissolved in methanol(anhydrous, 20 ml, 1.4 vol) and dichloroethane (anhydrous, 80 ml, 5.7vol) in the presence of a few drops of ethanesulfonic acid. The reactionmixture was stirred at reflux for 18 hrs under an inert atmosphere. Thenit was allowed to cool down, dried over MgSO₄, filtered and concentratedin vacuo. The crude was purified by distillation (b.p. 76° C., 20 mm Hg)to give a pure product as a colourless oil (7.53 g, 48% yield).

[0117]¹H NMR (CDCl₃): δ 0.88(3H, t), 2.66(2H, q), 3.63(3H, s) ref.Biochemistry, 2670, 1971.

D. Preparation of methyl(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

[0118] A 100 ml flask fitted with a magnetic stirring bar and aDean-Stark trap was charged with methyl 2-oxobutanoate (7.5 g, 73 mmol),toluene (50 ml, 7 vol) and 2-pyrrolidinone (8.4 ml, 111 mmol, 1.5 equiv)followed by dropwise addition of POCl₃ (1.6 ml, 20 mmol, 0.27 equiv).The reaction mixture was stirred under reflux with azeotropic removal ofwater via the Dean-Stark trap for 8 hours. After cooling down thesolution was washed with 10% aq KHSO₄ (2×3 vol). The aqueous phase wassaturated with NaCl and back extracted with toluene (1×6 vol). Thecombined organic phase was dried over MgSO₄, filtered and concentratedin vacuo to afford crude material (7.5 g) as an orange mobile oil. Thecrude oil was distilled (92-94° C., 0.1 mm Hg) and gave pure product(4.7 g, 60%) as a colourless oil.

[0119] Z:E ratio 6:1 by ¹H NMR.

E. Preparation of methyl(E)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenoate (Precursor A2)

[0120] A dry 100 ml flask fitted with a magnetic stirrer bar was chargedwith Z-A1 (2 g, 11.8 mmol), ethanol (2.2 ml, 37.3 mmol),tetrathydrofuran (THF, 40 ml, 20 vol) and dimethylaminopyridine (DMAP,150 mg, 1.23 mmol) under an nitrogen atmosphere. The reaction mixturewas cooled to 0° C. before adding dicyclohexylcarbodiimide (DCC, 2.46 g,11.9 mmol), then heated to ambient temperature. The reaction mixture wasstirred vigorously 21 hours. After that hexane (40 ml) was added toprecipitate a solid. The precipitate was filtered off and the filtratewas concentrated in vacuo to afford 3.03 g of colourless liquid oil. Theoil in water (40 ml) was washed with dichloromethane (DCM, 40 ml then2×20 ml), the solvent was dried by Na₂SO₄ and concentrated in vacuo toafford 2 g of E-A2 ethyl ester (100% yield).

F. Preparation of Precursor A3:(Z)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenenamide (Precursor A3)

[0121] A 20-litre flange flask was set up for stirring under inertatmosphere and was charged with A1 (222 g, 1.313 mol, 1 wt) andanhydrous THF (7.0 litres, 30 vol). The reaction mixture was allowed tocool below 5° C. and PCl₅ (300 g, 1.44 mol, 1.1 equiv) was addedportionwise keeping the reaction temperature below 10° C. The reactionmixture was stirred at −5 to 0° C. for one hour, allowed to warm up to15° C. to dissolve the remaining PCl₅, and then cooled back below 0° C.A condenser filled with dry ice/acetone was fitted and ammonia gas (˜200g) was bubbled slowly through the solution, keeping temperature below15° C. The suspension was stirred for an additional 15 min and theexcess ammonia was removed by bubbling nitrogen gas through for severalminutes. Methanol (3.7 litre, 17 vol) was added, the reaction mixturewas refluxed for 1.5 hrs, then cooled below 30° C., filtered, and washedwith THF/MeOH (2:1, 600 ml, ˜3 vol). The filtrate was evaporated to givea yellow solid. This material was dissolved in methanol (640 ml, ˜3 vol)and ethyl acetate (440 ml, 2 vol) and purified using dry-flashchromatography (SiO₂, 11 wt, 3.4 Kg) with EtOAc/MeOH (6:1) to affordcrude product (288 g). The crude product was recrystallised fromisopropanol (1.9 litres, ˜8.5 vol) to give white crystals (127 g). Thesolid was dried in vacuum oven at ambient temperature for 2 days toyield A3 (118 g, 54%).

[0122]¹HNMR (CDCl₃+few drops MeOD): δ 6.75 (1H,q) 3.5 (2H,t) 2.5 (2H,t)2.15 (2H,m) 1.17 (3H,d), traces of impurities.

[0123] Elemental analysis (% m/m): C 56.90 (57.13% theory); H 7.19(7.19% theory); N 16.32 (16.66% theory).

[0124] A3 (108 g) was recrystallised again from IPA (1 L, 9.3 vol) toafford a final batch used in the hydrogenation studies (100 g, 93%).

[0125] m.p. 172.0° C.-174.2° C.

[0126] Elemental analysis (% m/m): C 56.95 (57.13% theory); H 7.10(7.19% theory); N 16.38 (16.66% theory).

[0127] TLC: SiO₂, Toluene/AcOH/MeOH (4:1:0.5), UV and anisaldehydestain.

G. Preparation of Chiral Rhodium and Ruthenium Catalysts—Preparation of[Rh(I)L*COD]⁺OTf⁻ (0.15 M Solutions)

[0128] (Rh(I)COD₂]⁺OTf⁻ (35 mg, 0.075 mmol) and a chiral ligand (L*,0.083 mmol, 1.1 equiv) were weighed quickly in air and charged to aflask. The flask was sealed with a rubber septum and purged with argon.Anhydrous, degassed solvent (5 ml, 143 vol) was added via the septum.The reaction mixture was degassed (3×vacuum/argon) and stirred for 30min or until all solids had dissolved.

H. Preparation of Rh(I)(MeOH)₂[(R)-Binap]

[0129] A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar wascharged with [Rh(I)(nbd)₂]ClO₄ (251 mg, 0.649 mmol) and (R)-Binap (405mg, 0.65 mmol) under an argon atmosphere. Dichloromethane (anhydrous,degassed, 5 ml, 20 vol) was added via a syringe and the reaction mixturewas degassed (3×vacuum/argon). Tetrahydrofuran (anhydrous, degassed, 10ml, 40 vol) was added slowly followed by hexane (anhydrous, degassed, 20ml, 80 vol). The resulting suspension was kept at 0-5° C. for 16 hrs.The solvents were decanted under argon and methanol (anhydrous,degassed, 5 ml, 20 vol) was added. The Schlenk tube was purged withhydrogen (5×vacuum/hydrogen) and stirred at ambient temperature for 1.5hrs. The clear red orange solution was transferred to another Schlenktube (purged with argon) via a syringe. The catalyst solution was storedunder argon at 0-5° C. and used directly for hydrogenation (Tetrahedron,1245, 1984).

I. Preparation of [RuCl(R)-Binap)(C₆H₆)]⁺Cl⁻

[0130] A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar wascharged with [RuCl₂(C₆H₆)]₂ (0.33 g, 0.66 mmol) and (R)-Binap (0.815 g,1.3 mmol) under argon atmosphere. Degassed anhydrous benzene (20 ml, 60vol) and ethanol (130 ml, 330 vol) were added and the solution wasdegassed (3×vacuum/argon). The red brown suspension was heated to 50-55°C. for 45 min giving a clear brown solution. This was filtered through acelite pad under argon into another Schlenk tube. The solvents wereevaporated in vacuo to afford the catalyst as a yellow orange solid(1.08 g, 86%) which was stored under argon at 0-5° C. (J. Org. Chem.,3064, 1994.)

J. Preparation of [RuCl(R)-Binap)(C₆H₆)]⁺BF₄ ⁻

[0131] A dry 100 ml Schlenk tube fitted with a magnetic stirrer bar wascharged with [RuCl(R)-Binap)(C₆H₆)]⁺Cl⁻ (0.45 g, 0.52 mmol) and degassedanhydrous dichloromethane (20 ml, 44 vol) under argon atmosphere. Theresulting solution was degassed (3×vacuum/argon) and transferred via asyringe to another Schlenk tube containing a degassed suspension ofAgBF₄ (0.15 g, 0.77 mmol, 1.5 equiv) in dichloromethane (10 ml, 22 vol).The mixture was stirred vigorously for 0.5 h and then filtered through acelite pad under argon atmosphere. The filtrate was concentrated invacuo to give the catalyst as a green solid (0.42 g, 88%) which wasstored under argon at 0-5° C. (J. Org. Chem., 3064, 1994).

K. Preparation of Ru(OCOCH₃)₂[(R)-Binap]

[0132] A dry 200 ml Schlenk tube fitted with a magnetic stirrer bar wascharged with [RuCl₂(C₆H₆)]₂ (0.805 g, 1.60 mmol) and (R)-Binap (1.89 g,3.03 mmol, 0.95 equiv) under an argon atmosphere. Anhydrous, degasseddimethylformamide (30 ml, 38 vol) was added and the solution wasdegassed (3×vacuum/argon). The reaction mixture was heated to 100° C.for 10 min to give a dark red solution which was then cooled to ambienttemperature. A degassed solution of sodium acetate (5.2 g, 63.4 mmol, 20equiv) in methanol (50 ml, 60 vol) was charged to the reaction vesseland stirred for 5 min. Degassed water (50 ml, 60 vol) and toluene (25ml, 30 vol) were added and the reaction mixture was stirred vigorouslyfor 5 min. The toluene layer was transferred via a syringe to anotherdry Schlenk tube (purged with argon) and the aqueous phase was extractedwith toluene (2×25 ml). The combined toluene solutions were washed withwater (4×10 ml), the solvent was concentrated in vacuo at 45° C. anddried for 12 hrs under vacuum (0.1 mm Hg). The yellow brown solid wasdissolved in toluene (25 ml) without stirring and hexane (75 ml) wasadded slowly to form a second layer on top. The two phase mixture wasleft to stand at ambient temperature for 7 hrs and then at 0-5° C. for 3days. The catalyst crystallised out. The solvents were removed via asyringe under an argon atmosphere, the solid was washed with hexane (20ml) and dried under vacuum for 2 hrs to give the catalyst as an yellowbrown solid (1.76, 70%) which was stored under argon at 0-5° C. (J. Org.Chem., 4053, 1992).

L. Asymmetric hydrogenation of precursors A1, A2, A3.

[0133] The asymmetric hydrogenation follows the same protocol for eachprecursor. Therefore, only the asymmetric hydrogenation of A3 has beendescribed below.

[0134] Asymmetric hydrogenation of precursors A3.

[0135] Hydrogenation at atmospheric pressure of H₂

[0136] A dry 100 ml Schlenk tube fitted with a magnetic stirrer bar wascharged with the substrate (500 mg, 3 mmol) and purged with argon gas.Degassed solvent was added via a syringe followed by addition of acatalyst solution (0.5 to 2.5 mol %). The reaction mixture was degassed(3×vacuum/argon) and then purged with hydrogen (5×vacuum/hydrogen) usinghydrogen balloon. The reaction was stirred for 16-65 hrs at ambienttemperature. The hydrogen atmosphere was exchanged with nitrogen and thesolvent was evaporated in vacuo to afford a crude product, which wasanalysed by NMR spectroscopic analysis and chiral HPLC analysis.

[0137] Hydrogenation occurred at a pressure of 4 atm.

[0138] All manipulations were carried out in an AtmosBag™ (AldrichChemical Co.) under an argon atmosphere. The substrate (500-10000 mg,)was placed in stainless steel high pressure vessel (Vinci TechnologiesLtd, France) fitted with a teflon beaker (or glass dish) and a tefloncoated magnetic stirrer bar. Degassed solvent and a catalyst or acatalyst solution (0.25 to 2.5 mol %) was added. The vessel was sealedand purged with hydrogen by pressurising the vessel to 4.5-5.5 atm andthen releasing the pressure (5 times). Finally, the pressure wasadjusted to the desired level and the reaction mixture was stirred atambient temperature for 16-65 hrs. Upon completion the hydrogenatmosphere was exchanged with nitrogen and the solvent was evaporated invacuo to afford a crude product, which was analysed by NMR spectroscopicanalysis and chiral HPLC analysis.

[0139] Purification of final material: Purification of(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam).

[0140] Levetiracetam obtained by asymmetric hydrogenation as describedabove (5 g, 98% e.e.) was dissolved in water (20 ml, 4 vol) andextracted with ethyl acetate (3×10 ml, 3×2 vol). The organic phase wasthen back extracted with water (10 ml, 2 vol) and the aqueous phaseevaporated to afford a pale yellow solid (4.83 g, 80%). This solid (4 g)was dissolved in acetone (24 ml, 6 vol) and heated to reflux for onehour. The solution was allowed to cool down slowly to 0° C. at a rate of5-10° C./hr. The crystals were filtered, washed with acetone (1.6 ml,0.4 vol) and dried to give a white solid (3.23 g, 81%, >99.8% e.e., 54ppm Rh)

[0141] Purification of (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide(Levetiracetam):

[0142] Levetiracetam obtained by asymmetric hydrogenation as describedabove (5 g, 98% e.e.) was recrystallised from acetone (30 ml, 6 vol) asabove to yield a white crystalline solid (3.94 g, 81%, >99.8% e.e., 52ppm Rh). This material (3 g) was recrystallised again as above to afforda white crystalline solid (2.31 g, 77%, >99.8%e.e., 23 ppm Rh).

[0143] m.p. 118.4-119.9° C.

1. A process for preparing a compound having formula (A)

wherein X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN; R¹ is hydrogen oralkyl, aryl, heterocycloalkyl, heteroaryl, halogen, hydroxy, amino,nitro, cyano; R², R⁴ are the same or different and each is independentlyhydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy,sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonicacid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy,oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, vinyl, R³ is hydrogen, halogen, hydroxy, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl,alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl,alkoxy, oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, (C2-C5)alkenyl, (C2-C5)alkynyl, azido, phenylsulfonyloxy;R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; andR⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl,heteroaryl, alkylthio, arylthio; each alkenyl, alkynyl, azido mayindependently be optionally substituted by one or more halogen, cyano,thiocyano, azido, alkylthio, cyclopropyl, acyl, phenyl; which processcomprises the reaction of an α-ketocarboxylic acid derivative of generalformula (C) with a pyrrolidinone of general formula (D) according to thefollowing Scheme (1):


2. A process for preparing a compound having formula (A),

wherein X is —COOR⁷; R¹ is hydrogen or alkyl, aryl, heterocycloalkyl,heteroaryl, halogen, hydroxy, amino, nitro, cyano; R², R⁴ are the sameor different and each is independently hydrogen or halogen, hydroxy,amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino,carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl,arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio,arylthio, alkyl, alkoxy, oxyester, oxyamido, aryl, arylamino, aryloxy,heterocycloalkyl, heteroaryl, vinyl; R³ is hydrogen, halogen, hydroxy,amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino,carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl,arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio,arylthio, alkyl, alkoxy, oxyester, oxyamido, aryl, arylamino, aryloxy,heterocycloalkyl, heteroaryl, (C2-C5)alkenyl, (C2-C5)alkynyl, azido,phenylsulfonyloxy; R⁷ is hydrogen, hydroxy, alkyl, aryl,heterocycloalkyl, heteroaryl, alkoxy, aryloxy; and each alkenyl,alkynyl, azido may independently be optionally substituted by one ormore halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl,phenyl; which process comprises the reaction of an α-ketocarboxylic acidderivative of general formula (C′) with a pyrrolidinone of generalformula (D) according to the following Scheme (2):


3. A process for preparing a compound having formula (A),

wherein X is —CONH₂ or —CONR⁵R⁶; R¹ is hydrogen or alkyl, aryl,heterocycloalkyl, heteroaryl, halogen, hydroxy, amino, nitro, cyano; R²,R⁴ are the same or different and each is independently hydrogen orhalogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid,sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl,arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, oxyamido,aryl, arylamino, aryloxy, heterocycloalkyl, heteroaryl, vinyl; R³ ishydrogen, halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy,sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonicacid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy,oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, (C2-C5)alkenyl, (C2-C5)alkynyl, azido, phenylsulfonyloxy; R⁵and R⁶ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, andeach alkenyl, alkynyl, azido may independently be optionally substitutedby one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl,acyl, phenyl; which process comprises the conversion of an acid, wherethis acid is a compound of formula (A) where X is CO₂H, with the acidchloride with subsequent ammonolysis or reaction with a primary orsecondary amine of the general formula HNR⁵R⁶ according to the followingSchemes 3 or 4:


4. Process for preparing a compound of formula (B)

wherein X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN; R¹ is hydrogen oralkyl, aryl, heterocycloalkyl, heteroaryl, halogen, hydroxy, amino,nitro, cyano; R², R⁴ are the same or different and each is independentlyhydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy,sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonicacid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy,oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, vinyl; R³ is hydrogen, halogen, hydroxy, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl,alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl,alkoxy, oxyester, oxyamido, aryl, arylamino, aryloxy, heterocycloalkyl,heteroaryl, (C2-C5)alkenyl, (C2-C5)alkynyl, azido, phenylsulfonyloxy;R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, andR⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl,heteroaryl, alkylthio, arylthio; each alkenyl, alkynyl, azido mayindependently be optionally substituted by one or more halogen, cyano,thiocyano, azido, alkylthio, cyclopropyl, acyl, phenyl; which comprisesa reaction of a corresponding compound of general formula (A) accordingto the following Scheme (6):


5. Process according to claim 4, which comprises catalytic hydrogenationof (A).
 6. Process according to claim 4, wherein the compound of formula(A) is subjected to asymmetric hydrogenation using a chiral catalyst. 7.A process for preparing (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide or(R)-α-ethyl-2-oxo-1-pyrrolidineacetamide, which comprises subjecting acompound of formula A′ in the form of a Z isomer or an E isomer toasymmetric hydrogenation using a chiral catalyst according to thefollowing scheme: